The goal of this project is to generate a novel resource to study the human neurological disease narcolepsy. Narcolepsy is a debilitating sleep disorder that is often caused by the loss of neurons in the hypothalamus that produce the peptide neurotransmitter hypocretin (HCRT). The cause of HCRT neuron degeneration is unknown and has been difficult to study using existing techniques. With the advent of induced pluripotent stem (iPS) cell technology it is now possible to study in vitro the progression of diseases that have eluded rigorous study in vivo. Narcolepsy is ideally suited for in vitro modeling since, like ALS, it is caused by the specific loss of a defined neuron type. Here we propose to generate iPS cells from narcoleptic subjects and differentiate them into HCRT neurons in order to allow the future study of disease mechanisms. To achieve this goal, the Schier, Eggan, Scammell and White labs will collaborate over a two-year period to optimize the production of Hcrt neurons from ES cells (Aim 1) and produce iPS cells and HCRT neurons from narcoleptic subjects (Aim 2). The resulting patient-specific cells will serve as a public resource to study narcolepsy and neurodegeneration. PUBLIC HEALTH RELEVANCE: Narcolepsy is a debilitating sleep disorder that is often caused by the loss of specific neurons in the brain. This project aims to generate these neurons in culture from control and narcoleptic patients.